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- Niemann–Pick disease type C1 (1) (remove)
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Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an
autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein,
leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral
symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here,
we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions
of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin
(HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography
(HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we
Int. J. Mol. Sci. 2020, 21, 4502; doi:10.3390/ijms21124502 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020, 21, 4502 2 of 31
studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses
showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes
in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment
effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis
seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr
expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived
neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects
make examination of further treatment strategies indispensable